Targeted, localized and controlled drug delivery remains a major challenge. In many cases, efficacy of a drug can be improved and the risks of side effects reduced if the therapy is administered locally and/or continuously, rather than through conventional oral ingestion or injection, which produce burst releases. In some cases, dose-limiting toxicity levels are caused by agent losses in vascular travel during transplant procedures. Continuous and accurate local dosing is highly desirable, but remains a major challenge, particularly in the cardiovascular field where requirements for a material's biocompatibility and dosing control are stringent.
Current diffusion-based drug-delivery platforms suffer from very slow mass-transfer process. The published reports indicate involvement of solid/solid diffusion as well as channel (e.g., tubule) and solvent-help (e.g., capillary, osmotic) mechanisms but not convection. (Tepe, et al. 2007 Touch Briefings 2007—Interventional Cardiology, pp. 61-63; Scheller, et al. 2004 Circulation 110:810-814; Diaz, et al. 2005 J Biol Chem 280:3928-3937; Creel, et al. 2000 Circ Res 86:879-884; Lovich, et al. 2001 J Pharm Sci 90:1324-1335; Zilberman, et al. 2008 J Biomed Mater Res 84A:313-323; Davies 1997 N Engl J Med 336:1312-1314; Arakawa, et al. 2002 Arterioscler Thromb Vasc Biol 22:1002-1007; Parekh, et al. 1997 Gen Pharmac 29:167-172; Hearn, et al. 2009 Nature 458:367-371; Celermajer 2002 European Heart Journal Supplement F:F24-F28; Andersen, et al. 2006 BMC Clinical Pharmacology, published online 13 Jan. 2006; Oreopoulos, et al. 2009 J Structural Biology 168:21-36; Panchagnula, et al. 2004 J Pharm Sci 93:2177-2183; Migliavacca, et al. 2007 Comput Methods Biomech Biomed Engin 10:63-73; Arifin, et al. 2009 Pharmaceutical Research, published online 29 Jul. 2009.) In percutaneous transluminal angioplasty (PCTA) devices, for example, drug washout and overdose remain serious challenges. For oncology applications, for example, localized delivery of sufficient dose of anti-cancer drug via targeted delivery is highly desirable.
In recent years, carbon nanotubes have attracted attention due to their chemical, mechanical and geometric properties. Carbon nanotubes (CNTs) are allotropes of carbon with a cylindrical nanostructure and are members of the fullerene structural family. Nanotubes are categorized as single-walled nanotubes and multi-walled nanotubes. Carbon nanotubes are strong and stiff materials in terms of tensile strength and elastic modulus respectively. Various techniques have been developed to make nanotubes, such as arc discharge, laser ablation, high-pressure carbon monoxide, and chemical vapor deposition.
Researches have been reported on CNT-based drug delivery. For example, a recent study was reported on drug delivery using PEGylated-CNTs. (Liu, et al. 2008 Cancer Res. 68: (16), 6652). The reported system is based on covalently attaching drug molecules to PEGylated CNTs. Another research group used carbon nanotube-based tumor-targeted drug delivery system, which consisted of a functionalized CNTs linked to tumor-targeting modules as well as prodrug modules. (Chen, et al. 2008 J Am Chem Soc 130:16778-16785.) In both of the afore-mentioned approaches, functionalization of the CNTs is required, which presents a number of complications and procedural drawbacks.
One reported example of angioplasty drug delivery is a PTCA balloon coated with paclitaxel in an iopromide matrix. The balloon is inflated for 30-second contact with vascular wall to allow the matrix to dissolve and paclitaxel to migrate into the smooth muscle cell. (Scheller, et al. 2004 Circulation 110:810-814.) Major problems with this device include iopromide being hydrophilic and an X-ray contrast agent. The first causes some drug loss to blood stream (although claimed to be about 6%) and the second leads to adverse reactions for some patients. Furthermore, the balloon still contains about 10% paclitaxel after detachment and only about 15% remains in the plaque.
Another reported example of angioplasty drug delivery is a system using vascular stents made of paclitaxel-eluting composite fibers to deliver about 40% of drug, most of it over 30 days. (Zilberman, et al. 2008 J Biomed Mater Res 84A:313-323.) Since the main mass-transfer mechanism of this device is diffusion, the rate is inherently slow. These drawbacks are in addition to the well-documented risks and side effects associated with stents.
For angioplasty drug delivery monitoring, existing technologies typically use a fluorescent dye administered intravenously through a central venous line with a dose adapted to body weight. (Detter, et al. 2007 Circulation 116:1007-1014; Hattori, et al. 2009 Circ Cardiovasc Imaging 2:277-278; Hosono, et al. 2010 Interact CardioVasc Thorac Surg 10:476-477; Tanaka, et al. 2009 J Thorac Cardiovasc Surg 138:133-140; Waseda, et al. 2009 JACC Cardiovascular Imaging 2:604-612.) The illumination is provided by near-infrared laser diodes with a typical output of 80 mW in a field of view of 10 cm in diameter, eliminating tissue warming and eye protection concerns. The fluorescence emission of the excited dye is typically detected by an IR-CCD camera and digitized with a frame grabber that provides real-time recording.
Therefore, there remains an urgent and unmet need for improved drug delivery systems addressing the above-mentioned shortcomings, particularly in the field of angioplasty drug delivery.